Effect of berberine on hyperglycaemia and gut microbiota composition in type 2 diabetic Goto-Kakizaki rats.
Zhao Jin-Dong,Li Yan,Sun Min,Yu Chan-Juan,Li Jia-Yun,Wang Si-Hai,Yang Di,Guo Cheng-Lin,Du Xue,Zhang Wen-Jin,Cheng Ruo-Dong,Diao Xiao-Chuan,Fang Zhao-Hui
World journal of gastroenterology
BACKGROUND:A recent investigation showed that the prevalence of type 2 diabetes mellitus (T2DM) is 12.8% among individuals of Han ethnicity. Gut microbiota has been reported to play a central role in T2DM. Goto-Kakizaki (GK) rats show differences in gut microbiota compared to non-diabetic rats. Previous studies have indicated that berberine could be successfully used to manage T2DM. We sought to understand its hypoglycaemic effect and role in the regulation of the gut microbiota. AIM:To determine whether berberine can regulate glucose metabolism in GK rats the gut microbiota. METHODS:GK rats were acclimatized for 1 wk. The GK rats were randomly divided into three groups and administered saline (Mo), metformin (Me), or berberine (Be). The observation time was 8 wk, and weight, fasting blood glucose (FBG), insulin, and glucagon-like peptide-1 (GLP-1) were measured. Pancreatic tissue was observed for pathological changes. Additionally, we sequenced the 16S rRNA V3-V4 region of the gut microbiota and analysed the structure. RESULTS:Compared with the Mo group, the Me and Be groups displayed significant differences in FBG ( < 0.01) and GLP-1 ( < 0.05). A significant decrease in weight and homeostatic model assessment-insulin resistance was noted in the Be group compared with those in the Me group ( < 0.01). The pancreatic islets of the Me- and Be-treated rats showed improvement in number, shape, and necrosis compared with those of Mo-treated rats. A total of 580 operational taxonomic units were obtained in the three groups. Compared to the Mo group, the Me and Be groups showed a shift in the structure of the gut microbiota. Correlation analysis indicated that FBG was strongly positively correlated with Clostridia_UCG-014 ( < 0.01) and negatively correlated with ( < 0.01). Body weight showed a positive correlation with ( < 0.01) and a negative correlation with ( < 0.01). Importantly, our results demonstrated that Me and Be could significantly decrease ( < 0.01) and the / ratio ( < 0.01). Furthermore, ( < 0.01; < 0.05) was significantly decreased in the Me and Be groups, and ( < 0.01) was significantly increased. CONCLUSION:Berberine has a substantial effect in improving metabolic parameters and modulating the gut microbiota composition in T2DM rats.
10.3748/wjg.v27.i8.708
Partially hydrolyzed guar gum attenuates non-alcoholic fatty liver disease in mice through the gut-liver axis.
World journal of gastroenterology
BACKGROUND:The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis. Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease (NAFLD) by modulating gut microbiota. Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes. However, its effects on NAFLD remain to be fully elucidated. AIM:To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis. METHODS:Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic (Ath) diet (a mouse model of NAFLD) for 8 wk, with or without 5% PHGG. Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium. Body weight, liver weight, macroscopic findings in the liver, blood biochemistry [aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol, triglyceride, free fatty acids, and glucose levels], liver histology, myeloperoxidase activity in liver tissue, mRNA expression in the liver and intestine, serum endotoxin levels in the portal vein, intestinal permeability, and microbiota and short-chain fatty acid (SCFA) profiles in the cecal samples were investigated. RESULTS:Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels, liver fat accumulation, liver inflammatory (tumor necrosis factor-α and monocyte chemotactic protein-1) and fibrogenic (collagen 1a1 and α smooth muscle actin) marker levels, and liver myeloperoxidase activity, which were significantly attenuated by PHGG treatment. Furthermore, the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor (TLR) 4 and TLR9 expression, confirming that intestinal permeability was significantly elevated, as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran. PHGG treatment did not affect fatty acid metabolism in the liver. However, it decreased lipopolysaccharide signaling through the gut-liver axis. In addition, it significantly increased the abundance of cecal and subcluster XIVa. Treatment with PHGG markedly increased the levels of SCFAs, particularly, butyric acid, acetic acid, propionic acid, and formic acid, in the cecal samples. CONCLUSION:PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.
10.3748/wjg.v27.i18.2160
Fasudil prevents liver fibrosis activating natural killer cells and suppressing hepatic stellate cells.
Han Qiu-Ju,Mu Yong-Liang,Zhao Hua-Jun,Zhao Rong-Rong,Guo Quan-Juan,Su Yu-Hang,Zhang Jian
World journal of gastroenterology
BACKGROUND:Fasudil, as a Ras homology family member A (RhoA) kinase inhibitor, is used to improve brain microcirculation and promote nerve regeneration clinically. Increasing evidence shows that Rho-kinase inhibition could improve liver fibrosis. AIM:To evaluate the anti-fibrotic effects of Fasudil in a mouse model of liver fibrosis induced by thioacetamide (TAA). METHODS:C57BL/6 mice were administered TAA once every 3 d for 12 times. At 1 wk after induction with TAA, Fasudil was intraperitoneally injected once a day for 3 wk, followed by hematoxylin and eosin staining, sirius red staining, western blotting, and quantitative polymerase chain reaction (qPCR), and immune cell activation was assayed by fluorescence-activated cell sorting. Furthermore, the effects of Fasudil on hepatic stellate cells and natural killer (NK) cells were assayed . RESULTS:First, we found that TAA-induced liver injury was protected, and the positive area of sirius red staining and type I collagen deposition were significantly decreased by Fasudil treatment. Furthermore, western blot and qPCR assays showed that the levels of alpha smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP-2), MMP-9, and transforming growth factor beta 1 (TGF-β1) were inhibited by Fasudil. Moreover, flow cytometry analysis revealed that NK cells were activated by Fasudil treatment in and . Furthermore, Fasudil directly promoted the apoptosis and inhibited the proliferation of hepatic stellate cells by decreasing α-SMA and TGF-β1. CONCLUSION:Fasudil inhibits liver fibrosis by activating NK cells and blocking hepatic stellate cell activation, thereby providing a feasible solution for the clinical treatment of liver fibrosis.
10.3748/wjg.v27.i24.3581
Zinc oxide nanoparticles reduce the chemoresistance of gastric cancer by inhibiting autophagy.
World journal of gastroenterology
BACKGROUND:Gastric cancer (GC) is a common malignancy that results in a high rate of cancer-related mortality. Cisplatin (DDP)-based chemotherapy is the first-line clinical treatment for GC therapy, but chemotherapy resistance remains a severe clinical challenge. Zinc oxide nanoparticle (ZnO-NP) has been identified as a promising anti-cancer agent, but the function of ZnO-NP in GC development is still unclear. AIM:To explore the effect of ZnO-NP on chemotherapy resistance during GC progression. METHODS:ZnO-NP was synthesized, and the effect and underlying mechanisms of ZnO-NP on the malignant progression and chemotherapy resistance of GC cells were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, colony formation assays, transwell assays, wound healing assays, flow cytometry, and Western blot analysis in GC cells and DDP-resistant GC cells, and by tumorigenicity analyses in nude mice. RESULTS:Our data revealed that ZnO-NP was able to inhibit proliferation, migration, and invasion and induce apoptosis of GC cells. Meanwhile, ZnO-NP significantly reduced the half maximal inhibitory concentration (IC) of DDP for the inhibition of cell proliferation of DDP-resistant SGC7901/DDP cell lines. Autophagy was increased in DDP-resistant GC cells, as demonstrated by elevated light chain 3-like protein 2 (LC3II)/LC3I and Beclin-1 expression and repressed p62 expression in SGC7901/DDP cells compared to SGC7901 cells. Mechanically, ZnO-NP inhibited autophagy in GC cells and treatment with DDP induced autophagy, which was reversed by ZnO-NP. Functionally, ZnO-NP attenuated the tumor growth of DDP-resistant GC cells . CONCLUSION:We conclude that ZnO-NP alleviates the chemoresistance of GC cells by inhibiting autophagy. Our findings present novel insights into the mechanism by which ZnO-NP regulates the chemotherapy resistance of GC. ZnO-NP may serve as a potential therapeutic candidate for GC treatment. The potential role of ZnO-NP in the clinical treatment of GC needs clarification in future investigations.
10.3748/wjg.v27.i25.3851
Cold exposure and capsaicin promote 1,2-dimethylhyrazine-induced colon carcinogenesis in rats correlates with extracellular matrix remodeling.
Qin Jing-Chun,Yu Wei-Tao,Li Hui-Xuan,Liang Yu-Qi,Nong Fei-Fei,Wen Bin
World journal of gastroenterology
BACKGROUND:Extracellular matrix (ECM) remodeling and stiffening, which are correlated with tumor malignancy, drives tumor development. However, the relationship between ECM remodeling and rat experimental model of 1,2-dimethylhyrazine (DMH)-induced colorectal cancer (CRC) imposed by cold and capsaicin exposure remains unclear. AIM:To explore the effects of cold exposure and capsaicin on ECM remodeling and ECM enzymes in DMH-induced CRC. METHODS:For histopathological analysis, the sections of colon tissues were stained with hematoxylin and eosin, Masson's trichrome, Picrosirius red, and Weigert's Resorcin-Fuchsin to observe the remodeling of collagen and elastin. Additionally, the protein expression level of type I collagen (COL I), type 3 collagen (COL III0, elastin, matrix metalloproteinase (MMP) 1, MMP2, MMP9, and tissue-specific matrix metalloproteinase 1 (TIMP1) was assessed by immunohistochemistry. The messenger RNA (mRNA) levels of COL I, COL III, elastin, and lysyl oxidase-like-2 (LOXL2) in the colon tissues of rats was measured by reverse-transcriptase quantitative polymerase chain reaction. RESULTS:Although no differences were observed in the proportion of adenomas, a trend towards the increase of invasive tumors was observed in the cold and capsaicin group. The cold exposure group had a metastasis rate compared with the other groups. Additionally, abnormal accumulation of both collagen and elastin was observed in the cold exposure and capsaicin group. Specifically, collagen quantitative analysis showed increased length, width, angle, and straightness compared with the DMH group. Collagen deposition and straightness were significantly increased in the cold exposure group compared with the capsaicin group. Cold exposure and capsaicin significantly increased the protein levels of COL I, elastin, and LOXL2 along with increases in their mRNA levels in the colon tissues compared with the DMH group, while COL III did not show a significant difference. Furthermore, in immunohistochemical evaluations, MMP1, MMP2, MMP9, and TIMP1 staining increased in the cold exposure and capsaicin group compared with the DMH group. CONCLUSION:These results suggest that chronic cold and capsaicin exposure further increased the deposition of collagen and elastin in the colonic tissue. Increased COL I and elastin mRNA and protein levels expression may account for the enhanced ECM remodel and stiffness variations of colon tissue. The upregulated expression of the LOXL2 and physiological imbalance between MMP/TIMP activation and deactivation could contribute to the progression of the CRC resulting from cold and capsaicin exposure.
10.3748/wjg.v27.i39.6615
Transforming growth factor beta-1 upregulates glucose transporter 1 and glycolysis through canonical and noncanonical pathways in hepatic stellate cells.
World journal of gastroenterology
BACKGROUND:Hepatic stellate cells (HSCs) are the key effector cells mediating the occurrence and development of liver fibrosis, while aerobic glycolysis is an important metabolic characteristic of HSC activation. Transforming growth factor-β1 (TGF-β1) induces aerobic glycolysis and is a driving factor for metabolic reprogramming. The occurrence of glycolysis depends on a high glucose uptake level. Glucose transporter 1 (GLUT1) is the most widely distributed glucose transporter in the body and mainly participates in the regulation of carbohydrate metabolism, thus affecting cell proliferation and growth. However, little is known about the relationship between TGF-β1 and GLUT1 in the process of liver fibrosis and the molecular mechanism underlying the promotion of aerobic glycolysis in HSCs. AIM:To investigate the mechanisms of action of GLUT1, TGF-β1 and aerobic glycolysis in the process of HSC activation during liver fibrosis. METHODS:Immunohistochemical staining and immunofluorescence assays were used to examine GLUT1 expression in fibrotic liver tissue. A Seahorse extracellular flux (XF) analyzer was used to examine changes in aerobic glycolytic flux, lactate production levels and glucose consumption levels in HSCs upon TGF-β1 stimulation. The mechanism by which TGF-β1 induces GLUT1 protein expression in HSCs was further explored by inhibiting/promoting the TGF-β1/mothers-against-decapentaplegic-homolog 2/3 (Smad2/3) signaling pathway and inhibiting the p38 and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. In addition, GLUT1 expression was silenced to observe changes in the growth and proliferation of HSCs. Finally, a GLUT1 inhibitor was used to verify the effects of GLUT1 on a mouse model of liver fibrosis. RESULTS:GLUT1 protein expression was increased in both mouse and human fibrotic liver tissues. In addition, immunofluorescence staining revealed colocalization of GLUT1 and alpha-smooth muscle actin proteins, indicating that GLUT1 expression was related to the development of liver fibrosis. TGF-β1 caused an increase in aerobic glycolysis in HSCs and induced GLUT1 expression in HSCs by activating the Smad, p38 MAPK and P13K/AKT signaling pathways. The p38 MAPK and Smad pathways synergistically affected the induction of GLUT1 expression. GLUT1 inhibition eliminated the effect of TGF-β1 on HSC proliferation and migration. A GLUT1 inhibitor was administered in a mouse model of liver fibrosis, and GLUT1 inhibition reduced the degree of liver inflammation and liver fibrosis. CONCLUSION:TGF-β1 induces GLUT1 expression in HSCs, a process related to liver fibrosis progression. experiments revealed that TGF-β1-induced GLUT1 expression might be one of the mechanisms mediating the metabolic reprogramming of HSCs. In addition, experiments also indicated that the GLUT1 protein promotes the occurrence and development of liver fibrosis.
10.3748/wjg.v27.i40.6908
Melatonin prevents oxidative stress, inflammatory activity, and DNA damage in cirrhotic rats.
Colares Josieli R,Hartmann Renata M,Schemitt Elizângela G,Fonseca Sandielly R B,Brasil Marilda S,Picada Jaqueline N,Dias Alexandre S,Bueno Aline F,Marroni Cláudio A,Marroni Norma P
World journal of gastroenterology
BACKGROUND:Cirrhosis is an important health problem characterized by a significant change in liver parenchyma. In animals, this can be reproduced by an experimental model of bile duct ligation (BDL). Melatonin (MLT) is a physiological hormone synthesized from serotonin that has been studied for its beneficial properties, including its antioxidant potential. AIM:To evaluate MLT's effects on oxidative stress, the inflammatory process, and DNA damage in an experimental model of secondary biliary cirrhosis. METHODS:Male Wistar rats were divided into 4 groups: Control (CO), CO + MLT, BDL, and BDL + MLT. MLT was administered (20 mg/kg) daily beginning on day 15 after biliary obstruction. On day 29 the animals were killed. Blood samples, liver tissue, and bone marrow were collected for further analysis. RESULTS:BDL caused changes in biochemical and histological parameters and markers of inflammatory process. Thiobarbituric acid (0.46 ± 0.01) reactive substance levels, superoxide dismutase activity (2.30 ± 0.07) and nitric oxide levels (2.48 ± 0.36) were significantly lower ( < 0.001) n the groups that received MLT. DNA damage was also lower ( < 0.001) in MLT-treated groups (171.6 ± 32.9) than the BDL-only group (295.5 ± 34.8). Tissue damage and the expression of nuclear factor kappa B, interleukin-1β, Nrf2, NQO1 and Hsp70 were significantly lower in animals treated with MLT ( < 0.001). CONCLUSION:When administered to rats with BDL-induced secondary biliary cirrhosis, MLT effectively restored the evaluated parameters.
10.3748/wjg.v28.i3.348